DESCRIPTION: One of the earliest detectable consequences of aging in people is a decline in memory functions. The factors that are responsible for this decline are not yet understood. Aging rodents show similar functional declines in memory as humans in spatial memory tasks, so they can be used as a model system. The N- methyl-D-aspartate (NMDA) receptor is very important in spatial memory functions in young animals. We have characterized a selective vulnerability of NMDA receptors to the aging process as compared to the other glutamate receptors in mice. NMDA receptors are multi-subunit complexes. The epsilon1 (e1), epsilon2 (e2), and ?1 subunits are prominently expressed in the cerebral cortex and hippocampus, brain regions that are critical for memory. There is evidence that the NMDA receptor that is present in the aged brain may be detrimental to memory abilities. It remains to be determined whether it is the decline in expression with age that leads to detrimental influences of the remaining receptors or whether it is the environment of the aged brain that makes the receptor no longer beneficial for memory. The e2 subunit shows the greatest declines in both protein and mRNA expression during aging in rodents. The age-related decline in NMDA receptor binding density appears to be related to this decrease in e2 mRNA. In the prefrontal cortex, there appears to be an additional effect of aging on e2 protein expression in the area of the synapse. Whether this is due to an alteration in the ability of the e2 subunit to associate with the synaptic membrane or an increased turnover rate of the protein is not known. The ?1 subunit shows variable changes during aging. There is evidence that anti- inflammatory drugs can benefit ?1 and e2 subunit expression. It is not known how early this occurs or whether inflammation can account for the different patterns of ?1 splice variant expression that occur during aging. The hypothesis that will be addressed by this proposal is that multiple factors influence the expression patterns of specific subunits of the NMDA receptor and lead to age-related declines in learning and memory. The hypothesis will be addressed by the following three Specific Aims: 1) To determine whether increasing the expression of the e2 subunit in the aged brain is beneficial to memory performance, 2) To determine how aging alters the localizations and associations of the e2 subunit within the synaptic environment that influence memory performance, and 3) To determine whether inflammation contributes to age-related declines in NMDA receptor subunit expression and memory performance. These studies will have implications for the memory declines experienced in normal aging. They should also be useful in Alzheimer's disease because it is superimposed on the aging process. This information will also add to our knowledge about the role of specific NMDA receptor subunits within specific brain regions on learning and memory processes. PUBLIC HEALTH RELEVANCE Memory declines during aging can be very costly to the psychological and financial well being of individuals that are affected because it can interfere with their ability to live independently. Understanding how the aging process affects molecules that are involved in learning and memory processes allows us to better design interventions that will improve cognitive performance throughout the lifespan.